Homogonane derivatives



United States Patent 3,513,204 HOMOGONANE DERIVATIVES Eugene E. Galantay, Morristown, N.J., assignor to Sandoz-Wander, Inc., Hanover, N.J., a corporation of Delaware No Drawing. Continuation-impart of application Ser. No. 566,730, July 21. 1966. This application Dec. 20, 1966, Ser. No. 603,160

Int. Cl. C07e 171/02 US. Cl. 260-613 9 Claims ABSTRACT OF THE DISCLOSURE 13,8-(lower alkyl)-B-(6)-homogonenes have been found to possess properties useful for fertility control and in the therapy of menopausal problems. They are also useful for growth stimulation, postoperative recovery and healing of wounds and burns.

This a continuation-in-part of application Ser. No. 566,730, filed July 21, 1966, now abandoned.

This invention relates to B-(6)-homogonane derivatives of the formula 12 1 11 1 16 1 c D 2 1g 9 6bis wherein any hydrogen atom bound to C C and/or C is in the a-position; any hydrogen atom bound to C and/or C is in the fl-position;

R is either a hydrogen atom (H), carboxylic acid acyl having from 2 to 4 carbon atoms, e.g. acetyl, propionyl and butyryl or lR R is lower alkyl, e.g. methyl, ethyl, propyl, isopropyl and butyl; or cycloalkyl having from 5 to 7 ring carbon atoms, e.g. cyclopentyl;

Ring B has at least one unsaturated carbon atom (C and Rings C and D are either saturated or unsaturated;

processes and intermediates employed in the preparation thereof and pharmaceutically acceptable compositions containing same.

3,513,204 Patented May 19, 1970 The unsaturation in the remainder of the structure of compounds I is dependent to some extent on the saturation of the carbon atoms which form Ring A. Preferred compounds wherein Ring A is in form a are those which are otherwise saturated, have A have A304) or have A? preferred compounds wherein Ring A is in form b are those which are otherwise saturated, have A or have A and preferred compounds wherein Ring A is in either form 0 or form d are those which otherwise are saturated or have A The compounds of this invention are named from the parent steroid hydrocarbon Gonane (or Sterane) The individual rings of the depicted structure are designated, from left to right, A, B, C and D, as indicated in Formula I. In the structures of the compounds to which the present invention is directed there is an additional carbon atom in one of the rings; the compound is thus called a homogonane derivative. The fact that the additional carbon is in the B-ring makes it, more specifically, a B-homogonane. In order to specify that said additional carbon atom is interposed between C and O, (as opposed to, e.g., between C and C the compounds are designated as B-(6)-homogonanes. In practice it is unnecessary to include the (6) in the name, but it is understood that all of the subject homosteroids are so restricted. Each of the homosteroids of this invention additionally has at least one double bond; it is therefore a B-(6)-homogon-(monoor poly-)ene, hereinafter referred to generically as a B-(6)-homogonene.

Each compound I is unsubstituted in both the 5- and 10-position and is either an optically active isomer or a mixture of two such isomers, including racemates which consist of a levorotary and the corresponding dextrorotary form (enantiomers) in 1:1 proportion Totally synthetic preparation of compounds I results in racemates which are separated into their enantiomers by resolution according to well-established procedures known to those skilled in the art. Usually only one of the optically active forms exerts useful biological activity, i.e. the form in which C has the same absolute configuration as, e.g., in estrone or in other naturally-occurring steroids. It is thus advantageous to separate said form from its enantiomer to obtain a product having greater activity.

Compounds I are useful in the treatment of female hypogonadism, endometriosis, amenorrhea, dysmenorrhea, functional uterine bleeding, acne, osteoporosis, infertility and habitual abortion. They are also useful in achieving ovlulation block, pregnancy maintenance, nitrogen retention, growth stimulation, post-operative recovery, healing wounds and burns lipid shifting and lowering of the blood cholesterol level. They are particularly useful for fertility control and the therapy of menopausal problems. They are also intermediates for preparing compounds with the indicated utilities.

Compounds I are administered daily (or in long-acting 3 preparations) in standard dosage forms, e.g. in tablets or capsules perorally or in oily solutions, emulsions or suspensions subcutaneously or intramuscularly. Daily doses range from 0.05 to 80 milligrams.

Each of the pharmaceutically active compounds of this invention may be, e.g., incorporated, for oral administration, in a tablet as the sole active ingredient. A typical tablet is constituted by from 1 to 3 percent binder, e.g. tragacanth; from 3 to percent disintegrating agent, e.g. corn starch; from 2 to 10 percent lubricant, e.g. talcum; from 0.25 to 1.0 percent lubricant, e.g. magnesium stearate; an average dosage of active ingredient; and q.s. 100 percent of filler, e.g. lactose; all percentages being by weight. Tablets are prepared according to standard tabletting techniques, which are well-known in the art, employing the necessary amounts of conventional granulating liquids, e.g. alcohol SD-30 and purified water. As exemplary tabletting formulation for the instanct active compound is:

Parts Title Compound of Example .25 Tragacanth 2 Lactose 89.25 Corn Starch 5 Talcum 3 Magnesium Stearate 0.5

Alcohol SD-30, purified water, q.s.

Among the compounds of the present invention, 3- methoxy 13(lower alkyl)-B-homogona-1,3,5(10),8,14- pentaen-17-ones V are prepared according to 2 methoxy 6,7,8,9-tetrahydro-5H-benzocyclohepten- 5-one [J. Chem. Soc., 990 (1966)] II is reacted with a vinylmagnesium halide to yield 2-methoxy-5-vinyl-6,7,8,9- tetrahydro-SI-I-benzocyclohepten-S-ol III. (Other 2-loweralkoxy counterparts are obtained from corresponding starting materials.) III is subsequently reacted with a 2-(lower alkyl)-cyclopenta-l,3-dione [.Bull. Soc. Chim. France, 1036 1955)] in moderately acid (acetic acidxylene) or basic (triethylenediamine-xylene) media under reflux; thus-prepared 3 methoxy 8,14 seco-13-(lower alkyl)-B-homogona-l,3,5(l0),8 [and/or 9(11)]-tetraene- 14,17-dione IV is cyclized with acid, e.g. ptoluenesulfonic acid in boiling benzene and hydrochloric acid in methanol, at from 20 to 60, or polyphosphoric acid, to obtain compounds V.

Other compounds of this invention can be prepared from V, by the following modifications or combinations thereof:

Reduction or alkylation of the 17-oxo groupScheme B Reduction or hydrogenation of the double bonds in rings B, C, DScheme C Demethylation of the 3-methoxy group, followed, if desired, by realkylation or acylationScheme D Reduction of the aromatic ring A by the so-ca11ed Birch method, followed by hydrolysis of the thus-formed enol ether-Scheme E Introduction of A double bond in products obtained according to Scheme E, by bromination-dehydrobromination (or other dehydrogenation methods)-Scheme F Scheme B:

l I ll Scheme C:

GHIQO VIII Step 0 is catalytic reduction, preferably using a palladium/calcium carbonate or Raney nickel catalyst, in dioxane or benzene solvent.

Steps c and 0 are reductions with lithium sodium or potassium in liquid ammonia in the presence of aniline or pyrrole as a proton source.

For carrying out steps to 0 it is preferred to select compounds VI and VII with R and R substituents which would, themselves, not be changed under the conditions employed in said steps.

Scheme D:

CHQO R40 Step d is demethylation effected by, e.g., molten pyridine hydrochloride, boron tribromide or hydrogen bromide.

Step d is alkylation, cycloalkylation or acylation. Agaln, it is preferred to select, for steps d and d compounds of the present invention which, under the 9 B-homogona-2,5(10),8(l4)-trien-17-one 13fl-isopropyl-3methoxy 3-methoxy-13/3-methyl 17fl-hydroxy-B-homogon-4en-3-one 13 p-methyl 13 ,8, 17u-diethyl B-homogon-4-ene-3,17-dione 13B methyl 13 ,B-ethyl 13 ,B-isopropyl 13 ,B-propyl B-homogon-4-en-3-one 17 u-allyl- 1 7 fi-decanoyloxy-l 3 fi-methyl 17a-fiuorethynyl-13fi-isopropyl-17,8-pentadecanoyloxy 17,B-hydroxy-B-homogona-4, 8 14 -dien-3-one 13/3-methy1 13 B-ethyl- 1 7u-ethynyl 13 fi-ethyl-17a-propyl B-homogona-4,8 14) -diene-3, 17-dione 13,8-methyl 13 fl-ethyl 13 B-propyl 13 B-isopropyl 17B-hydroxy-B-homogona-4,8 14) ,9-trien-3-one 13 B-methyl 13B-ethy1-17a-ethynyl 13fi-ethyl-17u-propynyl 17a-ethyl-13B-methy1 17ot-fluoroethynyl-13fi-methyl 13 fl-isopropyl B-homogona-4,8 14) ,9-triene-3,17-dione 13 fi-methyl 13 fl-ethyl 13,6-isopropyl 13 fi-propyl B-homogona-4,8 14 ,9-trien-3-one 17u-buty1-17fl dodecanoyloxy-13B-isopropyl 17a-ethynyl-13,6-isopropyl-17fi-octaclecanoyloxy 17/3-hydroxy-Bhomogona-4,9-dien-3-one 135-methyl 13 ,B-ethyl B-homogona-4,9-diene-3,17-dione 13 fl-ethyl 13,6-isopropy1 B-homogona-4,9-dien-3-one 135-ethyl-17a-isopropyl-17B-undecanoyloxy 13f3-methyl-17,8-nonadecanoyloxy-17a-vinyl 17;8hydroXy-B-h0m0gon5( 10 -en-3-one 13/3-rnethyl 13 B-ethyl 17u-ethynyl-13/3-methyl 17a-ehloroethynyl-13,8-isopropy1 B-homogon-(10)-ene-3,17-dione 13,8-ethyl '13fl-methyl 13 fi-isopropyl B-homogon-S -en-3-one 17a-isopropyl-1 Sis-methyl-17,8-tridecanoyloxy 17fl-hydroxy-B-homogona-5 10) ,8 14) -dien-3 -one 13 fl-methyl 13fl-ethyl-17ot-ethynyl 17a-fluorethyny1-13,8-isopropyl l3B-rnethyl-17a-vinyl B-homogona-5( 10) 8( 14 -diene-3, 17-dione 1 Bit-methyl 13 fi-ethyl 13 B-propyl 13 fl-isopropyl All compounds within the scope of this invention are prepared from available, i.e. compounds which are either known per se or are prepared from known compounds by analogy procedures within the skill of the art, starting materials and/ or intermediates.

The examples which follow are merely illustrative of the invention, all temperatures being in d grees centigrade, the parts and percentages being by weight unless otherwise specified and the relationship between parts by weight and parts by volume being the same as that between the kilogram and the liter.

Unless stated otherwise, reaction mixtures obtained as specified in the examples are worked up in the following manner: the mixture obtained from the chemical reaction is distributed between water and a solvent, e.g. ben zene, ethyl acetate and chloroform, which is not miscible with water. (If solvents miscible with water are used in the reaction, they can be partially or totally removed by vacuum evaporation from the reaction mixture prior to distribution.) The aqueous phase is then separated and further extracted with the specified solvent until practically all of the desired organic product is collected in the solvent. The unified organic solution is then washed with water or aqueous solutions, e.g. (aq) sodium hydrocarbonate and dilute (aq) hydrochloric acid, to remove, if feasible, side products. After drying over an anhydrous salt, e.g. sodium sulfate, the solution is evaporated in vacuo to give the crude product as a residue, which is purified by crystallization recrystallization, chromatography or high-vacuum distillation. All of these are Wellknown operations to the skilled in the art.

EXAMPLE 1 Z-methoxy-S -vinyl-6,7,8,9-tetrahydro-SH-benzocyclohepten-S-ol Prepare vinyl magnesium bromide from 6.7 parts of magnesium turnings and 37.0 parts of vinyl bromide in parts by volume of tetrahydrofuran (THF). Add (over a period of 30 minut s and at 30) to the resultant vinyl magnesium bromide a solution of 14.7 parts of 2- methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one in 150 parts by volume of THF. Maintain the resulting mixture at room temperature (20) for 16 hours. After cooling to 5, add dropwise thereto 75 parts by volume of a saturated aqueous ammonium chloride solution and work up the thus-produced organic layer with ethyl acetate. The title compound is thus obtained as an oil.

EXAMPLE 2 3-m thoxy-13 -methyl-8,14-seco-B-homogona- 1,3,5(10),9(11)-tetraene-14,17dione.

1 l (b) 3-methoxy-13,3-methyl-B-homogona-1 ,3,5 (10) ,8, l4- pentaen-17-one CHaO (c) 3-methoxy-l3fi-methyl-B-homogona-1,3,5(10),8- tetraen-17-one Catalytically hydrogenate 3 methoxy 13/8-methy1-B- homogona-l,3,5(l0),8,14-pentaen-l7-one under the conditions described in Example 3(b) to obtain the title compound as an oil; the oxime, prepared in the usual way, has a M.P. of 183, dec.

EXAMPLE 3 (a) 3-methoxy-l 3p-methyl-B-hornogona-1,3,5 ,8, 14- pentaen-17B-ol Cool to -30 a suspension of 2.06 parts of 2(b) in 140 parts by volume of methanol. Add to the suspension (with stirring) 0.3 part of sodium borohydride. Continue stirring for 4 hours while maintaining the same temperature. Add acetic acid and water to the reaction mixture, filter and wash with water and then dry at room temperature to separate crystalline title compound (decomposition at 54). (To characterize, prepare the 17fi-acetate with acetic anhydride in pyridine; M.P. 139 to 142.)

(b) 3-methoxy-13fl-methyl-B-homogona-1,3,5(10),8-

tetraen-17;8-ol

Add 0.5 part of 3(a) to 0.15 part of palladized calcium carbonate prehydrogenated under 10 parts by volume of dioxane. Stir under at atmosphere of hydrogen and at room temperature until one mole of hydrogen is consumed. Filter olf the catalyst and evaporate the filtrate to dryness. Triturate the residue in petroleum ether to obtain the title compound M.P. 108 to 111; acetate M.P. 103 to 106.

(0) 3 -methoxy--rnethyl-B-homogona-1,3,5(10)- trien-17p-ol Add portionwise (with stirring) 2.2 parts of sodium to 2.2 parts of 3(b) in parts by volume of liquid ammOnia, 40 parts by volume of THF and 15 parts by volume of aniline.

After stirring for twenty minutes add ammonium chlo ride, diethyl ether and water to the resultant. Separate and dry the ethereal layer and then evaporate same to obtain the title compound; acetate M.P. 117 to 120.

((1) 3-methoxy-1 3 3-methyl-B-homogona-1 ,3 ,5 l0) trien-17-one CHao Add to the stirred mixture of 3 parts of 3(c) and 6 parts of anhydrous magnesium sulfate in 150 parts by volume of acetone, 3.6 parts by volume of Jones Reagent (8 N chromic acid-sulfuric acid solution). After 2 minutes at room temperature, add thereto 9 parts by volume of isopropyl alcohol and 6 parts of sodium hydrocarbonate. Evaporate the mixture and distribute the residue between diethyl ether and water. Evaporate the dried ethereal layer to obtain the title product, M.P. 78 to 82.

EXAMPLE 4 3-hydroxy-13fi-methyl-B-homogona-1,3,5(10)- trien-17-one HO i Maintain a melt of 0.30 part of 3(d) and 2.2 parts of pyridine hydrochloride at 210 for 40 minutes. After cooling the resulting melt to room temperature, add water and diethyl ether thereto. Wash the ethereal layer several times with 2 N hydrochloric acid and water; dry same and evaporate to obtain the title compound.

. 1 EXAMPLE 3-methoxy-13,8-methyl-17u-ethynyl-B--homogonav 1,3,5(),8-tetraen-17B-o1 Pass acetylene through a solution of 0.1 part of lithium and parts by volume of ethylene diamine for 1 hour. Then, at room temperature, and over a period of 30 minutes, add to the resultant a tetrahydrofuran (6 parts by volume) solution of 0.2 part of 3-methoxy-13B-methyl B-homogona-1,3,5(10),8-tetraen-17-one. After two hours add thereto 1 part of ammonium chloride and then 100 parts by volume of water. Extract the thus-prepared mixture with diethyl ether. Wash the ethereal extract with 2% hydrochloric acid and then with water; dry and evaporate the resultant to obtain the title compound; M.P., after crystallization from methanol-petroleum ether: 139 to 141.

EXAMPLE 6 (a) 3-methoxy-13 3-methyl-B-homogona-1,3,5( 10),8(14)- v tetraen- 17 B-ol To a mixture consisting of 2300 parts by volume of distilled liquid ammonia, 452 parts by volume of aniline, 820 parts by volume of tetrahydrofuran and 34.8 parts of 3 methoxy 136 methyl-B-homogona-1',3,5(l0),8,l4- pentaen-17/3-ol, Within 30 minutes, 8.9 parts of lithium metal. After 5 hours at refluxing ammonia temperature, add 8.7 parts of ammonium chloride and allow the ammonia to escape. Work up the mixture with diethyl etherbenzene 1:1, remove the aniline by subsequent washings with 2'N hydrochloric acid. Evaporate to dryness the washed and dried ether-benzene solution and dissolve the residue (35 parts) in a mixture of 175 parts by volume of acetic anhydride and 525 parts by volume of dry pyridine. After overnight at room temperature, pour the mixture on ice (300 parts) filter the crude acetate of the title product, which separates crystalline, M.P. 89 to 94, and wash same with methanol. Stir the acetate with a mixture of 1350 parts by volume of methanol and 550 parts by volume of 5% sodium hydroxide solution at room temperature for 18 hours, filter and wash with water to obtain the title product, M.P. 96 to 99, M.P. of the (pure) acetate 91 to 935.

(b) 3-methoxy-13,8-methyl-B-homogona-1,3,5 10,8 14)- tetraen-17-one To a solution of 3.0 parts of (a) in 120 parts by volume of acetone, add 3.6 parts by volume of 8 N chromic acid solution. The temperature rises from 25 to 36 within 5 minutes. Add 12 parts by volume of isopropyl alcohol and 6.0 parts of sodium hydrocarbonate, filter the mixture and thoroughly wash the solids with warm chloroform. Evaporate the combined filtrates and washings to dryness and dissolve the residue in benzene (25 parts by volume); then pass same through a column of alumina. Evaporate the eluates and crystallize with petroleum ether to give the title product, M.P. 98 to 3-methoxy 13,8 methyl B homogona-1,3,5(10),8,14- tetraen-17one. M.P. (71) 74 to 75, is analogously prepared.

EXAMPLE 7 3-methoxy- 1 3.,8-methyll 7a-ethyl-B-homogona- 1 3,5 10) 8 14 tetraenl 7,8-01

CHaO

EXAMPLE 8 3-methoxy-13fl-methyl-17a-allyl-B-homogona-1,3,5 10), 8 14)-tetraen-17fl-ol CHgO To a Grignard mixture (prepared in the usual way from 2.91 parts by volume of allyl bromide, 0.740 part of magnesium and 50 parts by volume of diethyl ether) add a solution of 1.2 parts of 3-methoxy-13B-methyl-B- homogona-1,3,5(10),8(14)-tetraen-17-one in 10 parts by volume of benzene-diethyl ether (1:1). After 30 minutes, add 60 parts by volume of xylene to the resultant and raise the temperature of the mixture, within 5 hours, to while allowing the lower-boiling solvents to distill off. After cooling to room temperature, add 120 parts by volume of saturated ammonium chloride solution and Wash the organic layer with subsequent portions of Water. Dry over sodium sulfate and evaporate oil the dried solution to obtain a red gum. Chromatograph the red gum on a silica gel column to obtain the title compound which, after crystallization from isopropyl alcohol, has the M.P. of 134 to 136.

1 5 EXAMPLE 9 To a mixture of 175 parts by volume of liquid ammonia, 45 parts by volume of tert.-butanol, 450 parts by volume of tetrahydrofuran and 5.0 parts of 3-methoxy-l3f3-methyl-B-homogona 1,3,5 (10),8(l4) tetraen- 17 3-01, add 090 part of lithium. After 1 hour at refluxing ammonia temperature, add an additional quantity of 0.45 part of lithium. After 4 hours at the same temperature add 50 parts by volume of methanol and evaporate the ammonia by the aid of a water aspirator. Thereafter add 300 parts by volume of water and then wash the mixture with water before concentrating in vacuo until crystallization of the product starts. Filter and dry over phosphorus pentoxide to obtain the title product, M.P. 83 to 92.

(b) 17 3 hydroxy 13,8-methyl-B homogona 5(10),8 (14) -dien-3 -one.

Stir a mixture of 2.8 parts of 3-methoxy-13B-methyl-B- homogona-2,5(10),'8(14)-trien-17B-ol in 50 parts by volume of acetic acid and 10 parts by volume of water at room temperature. After 25 minutes extract the mixture with chloroform. Wash the chloroform solution with sodium hydrocarbonate solution and water; then dry same over sodium sulfate and evaporate to obtain the title product. Crystallize the title compound from petroleum ether.

(c) 175 hydroxy 135 methyl B homogona 4,8 (14),9-trien-3-one.

Treat a solution of 0.3 part of 17,8-hydroxy-13fl-methyl-B-homogona(10),8(14)-dien-3-one in 40 parts by volume of pyridine at 5 with 3.5 parts of pyridinium bromide perbromide. After 5 minutes dilute the mixture with water and filter the resulting precipitate. Then wash the precipitate with water. Dissolve the thus-obtained crude dibromide in 200 parts by volume of pyridine and allow the resulting solution to stand at room temperature for 2 hours. Then concentrate the mixture to about 16 parts by volume in vacuo, dilute the concentrate with water and obtain the crude title product by extracting the resulting mixture with methylene chloride, drying the extract and evaporating the methylene chloride solution therefrom. Crystallide the title compound from diethyl ether.

water. Evaporate the dried chloroform solution and crystallize the residue to obtain the title compound.

EXAMPLE 10 (a) 17 ethyl 3 methoxy 13B methyl B homogona-2,5 10) ,8 l4)-trien-17fl-ol.

Add, at -60, 4 parts of lithium to a solution of 1.10 part of 3-methoxy-l7a-ethyl-13-methyl-B-homogona1,3, 5(10),8(14)-tetraen-l7fi-ol, 200 parts by volume of tetrahydrofuran (TI-IF) and 400 parts by volume of liquid ammonia. After stirring the resultant for 30 minutes, add 50 parts by volume of ethanol dropwise thereto. Allow the ammonia to evaporate from the mixture. Then add water thereto to precipitate the title compound. Filter the precipitate and recrystallize same to obtain purified title compound.

(b) ethyl 17B hydroxy 13p methyl B homogona-4,8 14) -dien-3-one.

B-homogona-2,5 10 ,8 14) -trien-l7-one Add dropwise 15 parts by volume of 6 N hydrochloric acid to a solution of 0.8 part of (a) in 40 parts by volume of 1:1 THF/methanol. After maintaining the resultant for 60 minutes at room temperature, dilute same with water and extract through chloroform to obtain the title compound.

1 7 EXAMPLE 11 (a) 3-methoxy 13fl-methyl-B-homogona-2,5(10)-dien- 17 6-01.

Add 13 parts of lithium to a solution of 22.3 parts of 3-methoxy-13,8-methyl-B-homogona-1,3,5( 10 -trien 1713- 01, 700 parts by volume of liquid ammonia and 450 parts by volume of THF. Treat the resultant dropwise with 145 parts by volume of ethanol. Evaporate the ammonia and then add ethyl acetate to the remainder. Wash and dry the ethyl acetate layer before evaporating same to dryness. Recrystallize the residue to obtain the title compound.

(b) 3 rnethoxy-13,8-methyl-B-homogona 2,5(10) dien- 17-one.

Reflux for 3 hours under nitrogen a mixture of 15 parts of 3 methoxy 13B methyl-B-homogona-2,5(10)- dien-17fl-ol, 500 parts by volume of toluene, 140 parts by volume of cyclohexanone and 7 parts of aluminum isopropoxide. Cool the refluxed material to room temperature, and then add thereto 20 parts by volume of water followed by 30 parts of sodium sulfate. Filter the thusobtained mixture and concentrate the filtrate to obtain the title compound as a solid.

(c) 17wethynyl-17fi-hydroxy-13fi-methyl-B-homogon- (10)-en-3-one.

-C CH O I Add (in one portion) 12.2 parts of lithium-acetylideethylene-diamine complex to a solution of 18.6 parts of 3-methoxy 13B methyl-B-homogona-2,5()-dien-17- one in 600 parts by volume of dimethyl acetamide. Pass acetylene for 2 hours (with continuous stirring) through the resulting solution. Then add 1000 parts by volume of ice water to the resultant and extract the obtained mixture with benzene. Evaporate the benzene extract to obtain 17ot-ethynyl-3-methoxy-13B-methyl B homogona- 2,5 (l0)-dien-17 3-ol. Reflux the latter with a mixture of 50 parts of oxalic acid and 1000 parts by volume of 4:1 methanol/Water to obtain the title compound.

18 EXAMPLE 12 OH ---czcrr Stir at room temperature for 3 hours a mixture of 28.3 parts of 17u-ethynyl-3-methoxy-136-methyl-B-homogona- 2,5 (10)-dien-175-ol, 500 parts of methanol and 34 parts by volume of 11 N hydrochloric acid. Then dilute the resultant with brine before extracting same 'With chloroform. Wash and dry the chloroform solution and evaporate same to obtain the title compound.

EXAMPLE 13 (a) 17/3-hydroxyl-l3fi-methyl-B-homogon-4-en-3-one Stir for four hours at refluxing ammonia temperature a mixture of 5 4 parts of 3-methoxy-l3-methyl-B-homogona- 1,3,5(10)-trien-17B-ol, 50 parts by volume of tetrahydrofuran, 200 parts by volume of liquid ammonia, 50 parts by volume of tert.-butyl alcohol and 1 part of lithium metal. Add to the resultant 50 parts by volume of methanol and then allow the ammonia to evaporate. Thereafter add thereto 200* parts by volume of water prior to concentration in=vacuo, whereupon the intermediary, 3-methoxy-13fl-rnethyl-B-homogona-2,5( l0)-dien 175-01, separates as an amorphous solid. Filter, wash thoroughly with Water and dry said amorphous solid. Stir the thus-dried solid for 2.5 hours at room temperature with a mixture of parts by volume of methanol, 8 parts by volume of water and 5 parts by volume of concentrated hydrochloric acid. Thereafter dilute the resultant with 80 parts by volume of water to separate the title compound as a solid. Purify the thus-obtained title compound by recrystallization from, e.g., diethyl etherpetroleum ether (9:1).

(b) 13 ti-methyl--propionyloxy-B-homogon-4-en-3-one 0C0 CHZCHg Admix 008 part of propionic acid anhydride With a solution of 0.2 part of 13/3-rnethyl-17B-hydroxy-B- h0rnogon-4-en-3-one and 3 parts by volume of pyridine. Retain the resultant 4 hours at room temperature. Then pour the resulting mixture on ice Water. Extract the resultant with chloroform to obtain the oily title compound.

1 9 EXAMPLE 14 13 ,8, l7a-diethyl-17B-hydroxy-B-homogona-4,9-dien-3-one Following the procedure of Example 2a, replace the 2-methylcyclopentane-1,3-dione with an equivalent of 2- ethylcyclopentane-1,3-dione to obtain the corresponding 13-ethyl-3-methoxy-8,14-seco B homogona 1,2,5 (10), 9(11)-tet1raene-14,17-dione.

Following the procedure of Example 2b, replace the title compound of Example 2a with an equivalent of the thus-obtained 13-ethyl-3-methoxy-8,14-seco-B-homogonal,3,5(10),9(11)-tetraene-14,17-dione to obtain 13;8-ethyl 3 methoxy-B-homogona-1,3,5(10),8,14-pentaen-17- one, M.P. (89) 91 to 92 (after recrystallization from methanol).

Following the procedure of Example 3a, replace the title compound of Example 2b with an equivalent of 13B-ethyl- 3-methoxy-B-homogona-1,3,5( 10),8,14-pentaen-17-one to obtain 13,8-ethyl-3-methoxy-B-homogona-1,3,5 10) ,18, 14- pentaen-l7B-ol.

Admix 0.07 part of acetic acid anhydride with a solution of 0.2 part of 13,8l-ethyl-3-methoxy-B-homogona-1,3,5 (10),8,14-pentaen-17B-ol and 3 parts by volume of pyridine. Retain the resultant at room temperature for four hours. Then pour the resulting mixture on ice water. Extract the resultant 'with chloroform to obtain the corresponding 175-acetate, M.P. 142 to 143.

Following the procedure of Example 3b, replace the title compound of Example 3a with an equvalent of 13/3- ethyl-3-methoxy-B-homogona 1,3,5 (l),8,14 pentaen- 1713-01 to obtain 13fl-ethyl-3methoxy-B-homogona-1,3, 5( 1 0) ,8-tetraen-17f3-ol.

Following the procedure of Example 30, replace the title compound of Example 3b with an equivalent of 13/9- ethyl-3-methoxy-B-homogona-1,3,5 ,8-tetraen-17fi 01 to obtain 13/3-ethyl-3-methoxy-B-hornogona 1,3,5 (10)- trien-17B-ol.

Following the procedure of Example 611, replace the title compound of Example 6a with an equivalent of 13,8- ethyl-3-methoxy-B-homogona-1,3,5(10)-trien-17B 01 to obtain 13fl-ethyl-3-meth0xy-B-homog0na-1,3,5 (10) trien 17-one.

Add 3.0 parts of 13B-ethyl-3-methoxy-B-homogona- 1,3,5 (10)-trien-17-one dissolved in 75 parts by volume of xylene to a Grignard mixture prepared from 1.23 parts of magnesium metal and 5.95 parts of ethyl bromide in 10 parts by volume of diethylether. Distill oil the ether, and reflux the remainder for eighteen hours. After cooling the refluxed remainder to room temperature, add saturated (aq.) ammonium chloride solution thereto, and extract the resultant with chloroform to obtain 135,170:- diethyl-3-methoxy-B-homogona-l,3,5(10)-trien-17fiol.

Following the procedure of Example 9a, replace the title compound of Example 6a with an equivalent of 13,9,17a-diethyl-3 methoxy B homogona 1,3,5(10)- trien-17B-ol to obtain 135,17a-diethyl-3-methoxy-B-homogona-2,S 10)-dien-l7 3-ol.

Following the procedure of Example 9b, replace the title compound of Example 9a with an equivalent of 13B,17a-diethyl-3-methoxy-B-homogona 2,5 (10) dien- 17B-ol to obtain l3,8,l7a-diethyl-l7a-hydroxy-B-homogon-5 l0) -en-3-one.

Add 0.7 part of pyridinium bromide perbromide to a solution of 0.58 part of 13B,17a-diethyl-17u-hydroxy-B- h0mogon-5(10)-en-3-one in 8 parts by volume of pyridine at 7. Pyridine hydrobromide precipitates. When the precipitation is considered to be complete, add thereto 25 parts by volume of Water. Separate by filtration the ressulting precipitate (consisting of an intermediary dibromo compound). Wash the latter precipitate with water and then with small amounts of ice-cold ethyl acetate. Redissolve the thus-washed precipitate in 40 parts by volume of pyridine, and maintain the resulting solution at 30 for 2 hours. Add parts by volume of water to the resultant and then extract same with chloroform. Evaporate the dried chloroform solution (extract) to obtain a foam. Admix the foam with diethyl ether to obtain the title compound as a colorless solid.

EXAMPLE 15 17a-chloroethynyl- 13 B-ethyl- 17,8-hydroxy-B-homogona- 4, 8 14) ,9-trien-3-one r CH2 OI'I Following the procedure of Example 6a, replace the 3-methoxy-l3p methyl B homogona 1,3,5(10),8,14- pentaen-l7fl-ol with an equivalent of l3fi-ethyl-3-methoxy- B-homogona-1,3,5 (l0),8,14-pentaen-17;3-ol (see Example 14) to obtain 13fl-ethyl-3-methoxy-B-homogona-1,3,5 (10),8(14)-tetraen-17[:?-ol, M.P. (65)-67 to 68, acetate M.P. (103)105 to 106".

Following the procedure of Example 9a, replace the title compound of Example 6a with an equivalent of 13,6- ethyl-3-methoxy-B-homogona 1,3,5 (10),8(14) tetraen- 175-01 to obtain 13/3-ethyl-3-methoxy B homogona- 2,5(10),8(14)-trien-17/3-ol.

Following the procedure of Example 9b, replace the title compound of Example 9a with an equivalent of 1319- ethyl-3-methoxy-B-homogona-2,5(10),8(14) trien 175 to obtain 13fl-ethyl-17p-hydroxy-b-homogona- 5(10),8 (14 -dien-3-one.

Following the procedure of Example 90, replace the title compound of Example 9b with an equivalent of ethyl-17/3-hydroxy-B-homogona 5 (10),8(14) dien 3- one to obtain l3f3-ethyl-l7/3-hydoxy B homogona- 4,8(14) ,9-trien-3-one.

Following the procedure of Example 9d, replace the title compound of Example 9c with an equivalent of 13 [3- ethyl-17 3-hydroxy-B-homogona-4,8(14),9 trien 3 one to obtain 13l9-ethyl-B-homogona-4,8(14),9-triene-3,17- dione.

Add, at 60, a solution of 0.7 part of trans-1,2-dichloro-ethylene in 2.0 parts by volume of diethyl ether to a sodamide mixture prepared from 0.3 part of sodium and 20 parts of liquid ammonia. Maintain the resulting admixture at the reflux temperature of ammonia and add thereto a solution of 2.9 parts of l3fl-ethyl-B-homogona- 4,8(14),9-triene-3,17-dione and 15 parts by volume of THF.

After 90 minutes at -30 pour the resultant into a mixture of ammonium chloride and ice, extract with diethyl ether, wash the ethereal extracts with dilute hydrochloric acid, aqueous sodium hydrocarbonate and water and dry over sodium sulfate. Chromatograph in an acidwashed alumina to obtain the title compound.

21 What is claimed is: 1. A B-(6)-homogonene of the formula wherein R is a member selected from the group consisting of lower alkoxy and monocycloalkyloxy having from 5 to 7 ring carbon atoms;

R is a member selected from the group consisting of methyl, ethyl, propyl and isopropyl;

R is a member selected from a group consisting of hydroxy and alkanoyloxy having from 2 to 20 carbon atoms;

R is a member selected from a group consisting of a hydrogen atom, lower alkyl, lower alkenyl, lower alkynyl, chlorethynyl and fiuorethynyl;

any hydrogen bound to a member selected from the group consisting of C C and C is in the Ot-POSllllOIl, an hydrogen bound to C is in the fi-position and any double bonds in the A, B. C. and D rings are selected from the group consisting of A A A1,3,5(10),8,14 and 1,3,5(10),s(14) 2. A B-(6)-homogonene according to claim 1 wherein R is hydroxy.

3. The compound according to claim 2 which is 3- methoxy 1348 methyl B homogona 1,3,5(10),8,14- pentaen-17/3-o1.

4. The compound according to claim 2 which is 3- methoXy 13p methyl B homogona 1,3,5(10),8- tetraen-17fl-ol.

5. The compound according to claim 2 which is 3- methoxy 13,6 methyl B homogona 1,3,5(10)-trien- -01.

6. The compound according to claim 2 which is 3- methoxy 13B methyl 17a allyl B homogona 1,3, 5(l0),8(14)-tetraen-17,6-ol.

7. The compound according to claim 2 which is 3- methoxy 13/3 methyl 17oz ethyl B homogona- 1,3,5(10),8(14)-tetraen-17fi-ol.

8. The compound according to claim 2 which is 3- methoxy 13/3 methyl B homogona 1,3,5(10),8(14)- tetraen-17fl-ol.

9. The compound according to claim 2 which is 3- methoxy 1319 methyl 17 allyl B homogonal,3,5(10),8,(14)-tetraen-17fl-ol.

References Cited UNITED STATES PATENTS 12/1966 Tadanier et a1.

JAMES A. PATTEN, Primary Examiner US. Cl. X. R. 

